Characterizing molecular subtypes of high-risk non-muscle-invasive bladder cancer in African American patients.

Background: We sought to determine whether differences in subtype distribution and differentially expressed genes exist between African Americans (AAs) and European Americans (EAs) in patients with high-risk nonmuscle-invasive bladder cancer (NMIBC).

Methods: We performed a retrospective cohort study including 26 patients (14 AAs and 12 EAs) from the University of Texas Medical Branch and the Durham Veterans Affair Health Care System from 2010 to 2020 among treatment naïve, high-risk NMIBC. Profiled gene expressions were performed using the UROMOL classification system.

Results: UROMOL racial subtype distributions were similar with class 2a being most common with 10 genes commonly upregulated in AAs compared to EAs including EFEMP1, S100A16, and MCL1 which are associated with progression to muscle-invasive bladder cancer, mitomycin C resistance, and bacillus Calmette-Guérin durability, respectively. We used single nuclei analysis to map the malignant cell heterogeneity in urothelial cancer which 5 distinct malignant epithelial subtypes whose presence has been associated with different therapeutic response prediction abilities. We mapped the expression of the 10 genes commonly upregulated by race as a function of the 5 malignant subtypes. This showed borderline (P = 0.056) difference among the subtypes suggesting AAs and EAs may be expected to have different therapeutic responses to treatments for bladder cancer. AAs were enriched with immune-related, inflammatory, and cellular regulation pathways compared to EAs, yet appeared to have reduced levels of the aggressive C3/CDH12 bladder tumor cell population.

Conclusions: While premature, gene expression differed between AAs and EAs, supporting potential race-based etiologies for muscle-invasion, response to treatments, and transcriptome pathway regulations.